Metabolite ratios to assumed stable creatine level may confound the quantification of proton brain MR spectroscopy

doi:10.1016/S0730-725X(03)00181-4

Magnetic Resonance Imaging

Volume 21, Issue 8, October 2003, Pages 923-928

https://doi.org/10.1016/S0730-725X(03)00181-4 Get rights and content

Abstract

In localized brain proton MR spectroscopy (¹H-MRS), metabolites’ levels are often expressed as ratios, rather than as absolute concentrations. Frequently, their denominator is the creatine [Cr], which level is explicitly assumed to be stable in normal as well as in many pathologic states. The rationale is that ratios self-correct for imager and localization method differences, gain instabilities, regional susceptibility variations and partial volume effects. The implicit assumption is that these benefits are worth their cost_w-_w propagation of the individual variation of each of the ratio’s components. To test this hypothesis, absolute levels of N-acetylaspartate [NAA], choline [Cho] and [Cr] were quantified in various regions of the brains of 8 volunteers, using 3-dimensional (3D) ¹H-MRS at 1.5 T. The results show that in over 50% of ∼2000 voxels examined, [NAA]/[Cr] and [Cho]/[Cr] exhibited higher coefficients of variations (CV) than [NAA] and [Cho] individually. Furthermore, in ∼33% of these voxels, the ratios’ CVs exceeded even the combined constituents’ CVs. Consequently, basing metabolite quantification on ratios and assuming stable [Cr] introduces more variability into ¹H-MRS than it prevents. Therefore, its cost exceeds the benefit.

Introduction

Metabolites’ levels in localized brain ¹H-MRS are often reported as ratios, rather than absolute concentrations [1], [2], [3], [4], [5], [6], [7], [8], [9]. The most frequent denominator is the [Cr] level, which is assumed to be stable in the normal, as well as in some pathologic states [1], [2]. Specifically, [NAA]/[Cr] and [Cho]/[Cr] recently have been reported in studies of multiple sclerosis, schizophrenia, ischemic vascular dementia, traumatic brain injury, normal aging, epilepsy and cancer [1], [2], [3], [4], [5], [6], [7], [8], [9].

The explicit rationale for this approach is that ratios correct for several unknown, difficult to obtain, or uncontrollable experimental conditions, e.g., static (B₀) and radio-frequency (RF, B₁) field inhomogeneities; instrumental gain drifts; imager and localization method differences; and voxel partial volume contamination with metabolite-free cerebral-spinal fluid (CSF) [10]. However, this approach also entails an implicit yet rarely mentioned assumption: its cost_w-_w increased variation due to the propagation of the experimental fluctuations in the numerator and denominator [11] is worth the above benefits. To test this hypothesis, the absolute levels of [NAA], [Cho] and [Cr] were quantified serially, intra-, as well as inter-individually, in ∼2000 voxels in various regions of the brains of 8 volunteers, using 3D ¹H-MRS at 1.5 T.

Section snippets

Human subjects

Eight healthy adults (6 women, 2 men), ranging in age from 21 to 47 years old (average 32), were studied with localized 3D ¹H-MRS. All subjects were briefed on the procedure they were to undergo and gave Institutional Review Board approved written informed consent.

MRI and 3D ¹H-MRS

All measurements were done in a 1.5 Tesla Magnetom 63SP (Siemens AG, Erlangen, Germany). Axial, sagittal and coronal T₁-weighted spin-echo (TE/TR =15/450 ms) MRI were obtained at 240 mm field-of-view (FOV) and 256 × 256 matrices. B₀

Intra-individual variability

The box plots of the intra-individual CV_jⁱ for [NAA], [Cr] and [Cho], Fig. 3a, exhibit median values of 13.8%, 18.5% and 20.1%, respectively, versus 15.1% for the CV_j1/j2ⁱ of [NAA]/[Cr] and 19.7%, for [Cho]/[Cr]. The elevation of the [NAA]/[Cr] CV_j1/j2ⁱ distribution versus the [NAA]’s, indicated by the arrow in Fig. 3a, was statistically significant. Voxel-by-voxel comparison showed that out of 469 voxels, 266 (56.7%) had higher CV_j1/j2ⁱ for [NAA]/[Cr], and 231 (49.3%) for [Cho]/[Cr], than the

Discussion

It has been common practice to use metabolite ratios such as [NAA]/[Cr] and [Cho]/[Cr] for quantification, instead of absolute metabolite levels [1], [3], [4], [5], [6], [7], [8], [9]. The most compelling reason was that ratios correct for several experimental unknowns, which, if needed to be obtained and corrected for [22], could render MRS too complicated for clinical setting. However, it must be noted that the self-correction assumption is only valid for correlated multiplicative factors,

Conclusion

The use of metabolite ratios to [Cr] in lieu of quantification potentially increases the variability of the result compared with the individual components, over half the time. The variations demonstrated here in healthy volunteers are in line with several recent reports in MS patients, suggesting that the stationary [Cr] assumption could be misleading in either population [25], [26]. Therefore, although ratios are well-intentioned means to correct the MRS data, most prominently for partial

Acknowledgements

We thank Drs. Andrew A. Maudsley and Brian J. Soher of UCSF and the SF Veteran’s Administration Medical Center for the use of their FITT spectral estimation software. This work was supported by NIH Grants CA92547, EB01015, NS39135, and NS37739.

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Original contributionMetabolite ratios to assumed stable creatine level may confound the quantification of proton brain MR spectroscopy

Abstract

Introduction

Section snippets

Human subjects

MRI and 3D 1H-MRS

Intra-individual variability

Discussion

Conclusion

Acknowledgements

Biol Psychiatry

J Magn Reson

J Magn Reson

Magn Reson Imaging

Neuroimage

Choline is increased in pre-lesional normal appearing white matter in multiple sclerosis

J Neurol

Diffuse axonal and tissue injury in patients with multiple sclerosis with low cerebral lesion load and no disability

Arch Neurol

Proton MR spectroscopy in multiple sclerosis

Neuroimaging Clin N Am

Evidence of axonal damage in the early stages of multiple sclerosis and its relevance to disability